2-amido-7-amino cephalosporanic acids and related compounds

ABSTRACT

This invention concerns 2-amido-6-aminopenicillanic acids, 2amido-6-haloimidopenicillins, 2-amido-6-alkoxyimidopenicillins, 2-amido-7-aminocephalosporanic acids, 2-amido-7haloimidocephalosporins and 2-amido-7-alkoxyimidocephalosporins which are useful as intermediates in the preparation of synthetic penicillins and cephalosporins having potent antibiotic activity. Further, it relates to a process for the preparation of these intermediates from penicillins and cephalosporins. Still further, it concerns the preparation of 6-aminopenicillanic acid and 7aminocephalosporanic acid by the respective hydrolysis of 2amido-6-aminopenicillanic acids and 2-amido-7aminocephalosporanic acids.

[ 1 Mar. 25, 1975 2-AMIDO-7-AMINO CEPHALOSPORANIC ACIDS AND RELATEDCOMPOUNDS [75] Inventors: Richard Bogash, Philadelphia;

Milton Wolf, West Chester; John H. Sellstedt, King of Prussia, all ofPa.

[73] Assignee: American Home Products Corporation, New York, NY.

22 Filed: Jan.18, 1971 211 Appl. No.: 107,537

Related US Application Data [63] Continuation-in-part of Ser. No.843,783, July 22,

1969, Pat. No. 3,669,980.

[52] U.S. Cl 260/243 C, 260/2391, 424/271,

424/246 {51] Int. Cl. C07d 99/16, C07d 99/24 [58] Field of Search260/2391, 243 C [56] References Cited UNITED STATES PATENTS 3,499,9093/1970 Weissenburger 260/243 C Wolf et a1. 260/2391 Cheney ct al.260/243 C Primary Examiner-Nicholas S. Rizzo [57] ABSTRACT Thisinvention concerns 2-amido-6-aminopenicillanic acids,2-amido-6-haloimidopenicillins, 2-amido-6- alkoxyimidopenicillins,Z-amido-7-aminocephalosporanic acids, 2-amido-7-haloimidocephalosporinsand 2-amido-7-alkoxyimidocephalosporins which are useful asintermediates in the preparation of synthetic penicillins andcephalosporins having potent antibiotic activity. Further, it relates toa process for the preparation ol these intermediates from penicillinsand cephalosporins. Still further, it concerns the preparation of6-aminopenicillanic acid and 7-aminocephalosporanic acid by therespective hydrolysis of 2amido- 6-aminopenicillanic acids and2-amido-7-aminocephalosporanic acids.

10 Claims, No Drawings 1 -AMIEYQCEPHALOP RAN DS AND RELATED COMPOUNDSThis application is a continuation-in-part of US. Pat. application, Ser.No. 843,783 filed July 22, 1969, now US. Pat. No. 3,669,980, grantedJune 13, 1972.

This invention relates to new and novel synthetic chemical compounds.More particularly, it concerns Z-amido-o-aminopenicillanic acids,2-amido-7- aminocephalosporanic acids and related compounds which areuseful intermediates in the ultimate preparation of syntheticpenicillins and cephalosporins which have potent antibiotic activity.Further, it concerns the preparation of o-aminopenicillanic acid whichis a wellknown and important intermediate in the preparation ofsynthetic penicillins. Still further, it relates to a chemical method ofpreparing the intermediates of the present invention from natural andsynthetic penicillins and cephalosporins.

The new and novel intermediates within the scope of the presentinvention are exemplified by the following formulae:

ployed in the cephalosporin formula (ll) may be I-,hal0-2-(Z-thienyl)ethylideneamino As will also be known to thoseskilled in the art, included in those groups that are defined asiminoether" are those lower alkoxyimido substituents which are derivedfrom natural and synthetic penicillins and cephalosporins. Examplesthereof, when R is employed in the penicillin formula I are:1-(lower)alkoxy-2-allylmercaptoethylideneamino,l-(lower)alkoxy-2-(y-chlorocrotyL mercapto)ethylideneamino,l-(lower)alkoxy-2- phenoxyethylideneamino,a-(lower)alkoxyphenethylideneamino, l-(lower)alkoxy-3-hexenylideneamino. l-(lower)alkoxyhexylideneamino,l-(lower)alkoxyoctylideneamino and a-(lower)-alkoxy-p-hydroxyphenethylideneamino and R as employed in thecephalosporin formula (ll) may be l-(lower)alkoxy-2-(2-thienyl)ethylideneamino; R is selected from the groupconsisting of methyl, hydroxymethyl and (lower)alkanoyloxymethyl.

As known to those skilled in the chemical art, included in those groupswhich are electron withdrawing that do not have an active hydrogen atomwhen X and Y are taken separately are, for example: cyano; nitro;

R S CH3 8 l 3 X\ and R l N O (ILI"N\YI., 0/ R1 0 X C-N n Y" O wherein Ris amino; haloimidoyl, such as, chloroimidoyl and bromoimidoyl; oriminoether; X and Y when taken separately are both electron withdrawinggroups that do not have an active hydrogen atom and when taken togetherwith the nitrogen atom to which they are attached complete a cyclicelectron withdrawing group that does not have an active hydrogen atom;and the acid-addition salts thereof.

As is well-known to those skilled in the art, included in those groupsthat are defined as haloimidoyl are those haloimido substituents whichare derived from natural and synthetic penicillins and cephalosporins,for example, R as employed in the penicillin formula (I) may be definedas 2-allylmercapto-lhaloethylidcncamino, l-halo-2(y-chlorocrotylmercanto)clltylidcneamino, l-halo-2- phenoxycthylideneamino,a-halophenethylideneamino, l-halo-3-hexenylideneamino,lhalohexylideneamino, l-halo-octylideneamino anda-chloro-p-hydroxyphenet'hylideneamino and R asemtrifluoromethylsulfonyl; 2,3,5,6tetramethylbenzoyl; carb(lower)alkoxy;di(lower)alkylcarbamyl; lower alkylsulfonyl; di(lower)alkylsulfamyl;di(lower)alkylamino(lower)alkylsulfonyl; lower alkanoyl e.g.tert.-butyryl; cyclo(lower)a lkanoyl, aroyl e.g. naphthoyl and furoyl;substituted aroyl; arylsul'fonyl e.g. naphthylsulfonyl, pyridylsulfonyl,furylsulfonyl; substituted arylsulfonyl;

2,4,6-trimethylbenzoyl;

wherein R and R when taken separately can be hydrogen; lower alkyl;lower alkoxy; halogen; phenyl;phen(- lower)alkyl; lower alkoxyphenyl;aryl, e.g. 2-pyridyl, 4-pyridyl; trihalomethyl; nitro;di(lower)alkylamino; sulfamido, carb(lower)alkoxy, cyano, loweralkylthio, lower alkylsulfonyl, and when R and R are joined, theycomplete a benzene ring fused to the existing benzene ring to formtherewith a naphthalene ring; Z is selected from the group consisting ofsulfonyl and carbonyl; W is selected from the group consisting of sulfonyl, carbonyl and methylene; V is selected from the group consisting ofoxygen, sulfur and methylene; u is selected from the group consisting ofcarbonyl and methylene; and the broken line indicates the presence of asingle or double bond between these two positions.

The preferred embodiments of the compounds of this invention are thoseof formula (III) wherein X and Y are concatenated to form a saccharyl orsubstituted saccharyl group. These compounds are exemplified by thefollowing formula:

3 on I K l i; l c 3/S2\/\ R8 O-N, O MR9 C ll 0 and the acid-additionsalts thereof; wherein R and R are defined as above.

The term lower alkyl" as employed herein, alone or in conjunction withother designated groups, is intended to encompass straight chain orbranched chain alkyl groups consisting of from one to about six carbonatoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentylZ-ethylpropyl, hexyl, 2-propyl-propyl, and the like. Similarly, theterms lower alkoxy" and lower alkanoyl as used herein, alone or inconjunction with other designated groups, is intended to encompassstraight chain or branched chain alkoxy groups also consisting of fromone to about six carbon atoms. The term halogen as conventionally usedherein, alone or attached to other designated groups, is intended toencompass: chlorine, bromine, iodine and fluorine. As will also beunderstood, the ringed substituents, whether carbocylic, e.g. phenyl,benzyl, etc. or heterocyclic, e.g. Z-pyridyl, 4-pyridyl, and the likemay also be substituted by one or more of such usual substituents asthose set forth for R and R above. Similarly. the naphthalene ringresulting when R and R" are joined as referred to above, may also carryone or more of the same substituents also referred to above. By thephrase electron withdrawing group" is meant an electrophilic group whichwill inductively withdraw electrons from the carbonyl position of the2-amido groups of the compounds of this invention thereby making thesegroups more liable to cleavage by a nucleophilic agent, for example,water, alkali metal hydroxides, tertiary amines, quinoline and the like,to afford a carboxylic acid group.

By the phrase groups that do not have an active hydrogen" is meant thosegroups which show the absence of reactive hydrogen in the Zerevitinovdetermination.

The first new and novel process of the present invention concerns thesynthesis of the 2-amido amine compounds of the present invention, inparticular, the 2-amido-o-aminopenicillanic acids (IV) and 2-amido-7-aminocephalosporanic acids (V), which are depicted by the followingformulae:

3 ,873 ,5 3 3 5 6 wherein R is the same as hereinabove described; X andtional recovery procedures, e.g. the reaction mixture is Y when takenseparately are both electron withdrawing filtered and the collectedsolid is dried to afford the groups that do not have an active hydrogenatom and product (Vlll or 1X) Alternatively, the unseparated when takentogether with the nitrogen atom to which product is employed directly inthe following reaction. they are attached complete a cyclic electronwithdraw- 5 The above prepared Z-amino haloimido compound ing group thatdoes not have an active hydrogen atom; (Vlll or IX) is contacted with analkanol to afford the which comprises: contacting a phosphoruspentahalide, corresponding Z-amido alkoxyimido hydrohalide comsuch as,phosphorus pentachloride and phosphorus pound, e.g. the hydrochloride orthe hydrobromide sepentabromide, with a diamide compound, in particular,lected from those having the formulae:

CH 5 1Q- N-- K 3 .R C=

l CH x N O C-N\ O H Y X o c-u ll Y O a Z-amido derivative ofa natural orsynthetic penicillin wherein R, R", R", X, Y and Z are defined as above;(Vl) or cephalosporin (Vll), selected from those havand R is loweralkyl. The new and novel Z-amido aling the formulae: koxyimidohydrohalide compounds of this invention, in

l lOEl I32 R CNH.

r- X N C-N 0 ll Y 0 (VII) wherein R is the same as hereinabove defined;X and particular, the 2-amido-o-alkylimidopenicillin hydro- Y aredefined as above; R is a substituent selected 40 halides (X) and theZ-amido-7-alkoxyimidocephalosfrom those contained in natural andsynthetic penicilporin hydrohalides (Xl), prepared by the abovelins, forexample, allylmercaptomethyl, y-chlorocrotyldescribed substitutionreaction may be employed dimercaptomethyl, phenoxymethyl, benzyl,2-pentyl, rectly in the subsequent reaction or may be recovered amyl,heptyl, and p-hydroxybenzyl', and R is a subby standard separationprocedures, e.g. filtration and stitutent selected from those containedin natural and 45 drying the collected precipitate. syntheticcephalosporins e.g. 2-thienylmethyl; in a The 2-amido alkoxyimidohydrohalide compound (X reaction-inert, aprotic solvent, in the presenceofa base or XI) as prepared above. is then hydrolyzed by routine toafford a Z-amido haloimido compound selected from procedures, e.g.contact with water to afford the correthose having the formulae:sponding hydrohalide of the Z-amido amine compound.

S Rlofl s ca 11 i CH and i o C-N l ll 7 Y /X 0 C-N ll Y (VIII) (IX)wherein R, R, R", X and Y are defined as above and This hydrohalide,e.g. the hydrochloride or hydrobro- Z is a halogen, e.g. chloro andbromo. The new and .65 mide is then readily converted to itscorresponding novel Z-amido haloimido compounds of this invention, basicform (IV or V) by neutralization processes which in particular, the2-amido-o-haloimidopenicillins (Vlll) are well-known to those skilled inthe art of chemistry. are 2-amido-6-halo imidocephalosporins (1X)prepared For example, the hydrohalide is treated for a short time by theabove reaction may be separated by convenwith water containing a base,such as, triethylamine,

sodium bicarbonate or the like, preferably in the presence of awater-miscible solvent.

As employed herein the term natural penicillins includes those which areproduced by fermentation as well as those that are biosyntheticallyprepared by the addition of certain precursors to the fermentationbroth. Examples of these types of penicillins are: Penicillin O, whichis designated by the 2-carboxy derivative of the compound of formula(VI) where R is allylmercaptomethyl; Penicillin S, wherein R isy-chlorocrotylmercaptomethyl; Penicillin V, wherein R is phenoxymethyl;Penicillin G, wherein R is benzyl; Penicillin F, wherein R is2-pentenyl; Dihydropenicillin F, wherein R is amyl; Penicillin K,wherein R is heptyl; and Penicillin X, wherein R is p-hydroxybenzyl. Theterm synthetic penicillins" is used to include any penicillin which maybe prepared by the acylation of 6-aminopenicillanic acid. Examples ofthese types of penicillins are: Ampicillin, which is designated by the2-carboxy derivative of the compound of formula (VI), wherein R is aa-aminobenzyl; Nafcillin, wherein R is 2ethoxynaphthyl andDicloxacillin, wherein R is 3-(2,6-dichlorophenyl)-S-methyl-4-isoxazole. It should be noted that although it is (XII) isnot limited in operability to these starting materials and will operateequally well utilizing synthetic penicillins as reactants. By the termcephalosporins is meant known derivatives of cephalosporanic acid, suchas, cephalothin wherein R in formula (IV) is 2- thienylmethyl, as wellas, those compounds wherein the 3-position acetoxymethyl group has beenmodified by known chemical procedures to afford the correspondingcompounds which are substituted at the 3 position with othersubstituents, for example, a methyl, hydroxymethyl or otheralkanoylmethyl groups. The expression reaction-inert, aprotic solvent"encom passes those liquids which do not yield protons and will dissolvethe reactants without interfering with their interaction, such as,methylene chloride, chloroform, dioxane, tetrahydrofuran, ether,dimethoxyethane, benzene, xyleneand toluene. The term base is meant toinclude both organic and inorganic proton acceptors which are capable oftaking up protons, e.g. quinoline, dimethylamine, dimethylaniline,pyridine, N- ethylmorpholine and potassium carbonate. Since many of thecompounds (I and II) of the present invention are basic, advantage maybe taken of the water solubility of salts of these compounds formed withacids in the isolation and purification of the above compounds and inthe preparation of aqueous solutions thereof. Such acids are well-knownin the art, for example, hydrochloric, hydrobromic, sulfuric, nitric,phosphoric, benzenesulfonic, toluenesulfonic, methylsulfonic,ethylsulfonic acids and the like. These salts may be prepared byprocedures commonly employed in the art, for example, reacting thecompound with an equivalent of the selected acid in aqueous solution andconcentration of the solution. Other known procedures may also beemployed.

The second new and novel process of the present invention concerns thepreparation of 6- aminopenicillanic acid (XII) and7-aminocephalosporanic acid (XIII) having the following Z-carboxy aminecompound formulae:

which comprises contacting a 2-amido amine compound (IV or V) of theformulae:

where R is selected from the group consisting of methyl, hydrodymethyland (lower)alkanoyloxymethyl; X and Y when taken separately are bothelectron withdrawing groups that do not have an active hydrogen atom andwhen taken together with the nitrogen atom to which they are attachedcomplete acyclic electron withdrawing group that does not have an activehydrogen atom; with water, in the presence of a hydrolytic catalyst,until the hydrolysis is complete. As used herein the term hydrolyticcatalyst refers to substances which will assist in the hydrolysis of the2- amido moiety of the Z-amido amine compounds ol'thls invention. Manysuch substances will readily suggest themselves to those skilled in theart of chemistry, for example, quinoline, pyridine, imidazole and alkalimetal acetates, such as, sodium acetate.

Y s and 2;'(

r o R C-N n Y I o The preferred process of the present inventionconcerns the preparation of the above designated 2- saccharimido aminecompounds, such as, 2- saccharimido-(i-amino-penicillanic acids (11]).These compounds (lll) are synthesized by first preparing thesaccharimide of a natural or synthetic penicillin, e.g. benzylpenicillin, phenoxymethyl penicillin and the like. This is accomplishedby contacting a starting penicillin or the alkali metal salt thereofwith a selected saccharin halide derivative, in a suitable organicsolvent, e.g. methylene chloride. This reaction is conducted in thepresence of an acid acceptor, such as, triethylamine when the startingpenicillin employed is its acid form. When the mixture is complete theresulting solution is washed, dried, and concentrated to dryness. Theresidue is 2-saccharimido amide compound in particular, a2-saccharimido-penicillin, which may then be crystallized from asuitable organic solvent system, e.g. ether in benzene.

The above prepared Z-saccharimido amide compound is dissolved in areaction-inert, aprotic solvent, e.g. methylene chloride, in thepresence ofa base, e.g. quinoline and then admixed with phosphoruspentachloride to afford the corresponding 2-saccharimido chloroimidocompounds, e.g. 2-saccharimido-6- chloroimidopenicillin, which is thenreacted with an alkanol, e.g. methyl alcohol, ethyl alcohol, propylalcohol, butyl alcohol and the like, so that, the chlorine atom of theimido chloride moiety is replaced by the alkoxy group supplied by thealkanol employed to af ford an appropriate hydrochloride salt of a 2-sac charimido alkoxyimido compound, e.g. 2saccharimido-o-alkoxyimidopenicillin hydrochloride.

The above prepared 2-saccharimido amine compound, is then readilyconverted to the corresponding 2-carboxy amine compound by contact withwater in the presence of a hydrolytic catalyst. For example, 2-saccharimido-o-aminopenicillanic acid is treated at a pH of from about1.5 to about 9, in water or a mixture of water and a water-misciblesolvent until hydrolysis is complete to afford 6aminopenicillanic acid.

The preferred method of the present invention to prepare the2-saccharimido-6-aminopenicillanic acids (Ill) and o-aminopenicillanicacid (Xll) which has hereinbefore been described may be represented bythe following reaction scheme:

The starting diamide compounds, e.g. 2- amidopenicillins and2-amidocephalosporins are prepared by standard procedures, e.g. reactingimidoyl halides with natural or synthetic penicillins andcephalosporins. Thus, for example, the starting 2-saccharimidopenicillins for the preparation of the preferred compounds (lll) of thisinvention are synthesized by react ing a penicillin with a3-halosaccharin derivative, e.g.3-chloro-1,2-benzisothiazole-l,l-dioxide or an appropriately substitutedderivative thereof in an organic solvent, such as, anhydrous methylenechloride which contains an acid acceptor, e.g. triethylamine. When thecondensation reaction is complete, the 2- saccharimidopenicillin may berecovered by standard procedures, for example, the reaction mixture iswashed, dried, concentrated and the residue crystallized from a suitableorganic solvent, e.g. ether in benzene. The natural or syntheticpenicillins and cephalosporins employed in the synthesis of theabovedescribed starting materials are commercially available or arereadily prepared by well-known procedures. Similarly, the imidoylhalides are commercially available or, in those instances where they arenot available, they may be synthesized readily by standard organicprocedures described in the chemical literature and known to thoseskilled in the art.

The new and novel compounds (I and 11) and their acid-addition salts ofthe present invention, which inelude: 2-amido-o-aminopenicillanic acids,2-amido-6- haloimidopenicillins, 2-amido-6- alkoxyimidopenicillins,2-amido-7-aminocephalosporanic acid, 2-amido-7-haloimidocephalosporinsand 2- amido-7-a1koxyimidocephalosporins; are extremely usefulintermediates in the preparation of 6- aminopenicillanic acid and7-aminocephalosporanic acid which by procedures which are nowconventional in the art may be acylated to prepare synthetic penicillinsand cephalosporins. In this regard, for example, 6- aminopenicillanicacid may be acylated with an acid chloride by the procedures describedin US. Pat. No. 3,248,386 to afford 2-ethoxy naphthyl penicillin, or anN-carboxy anhydride as described in US. Pat. No. 3,206,455 to obtainD(-)-a-aminobenzylpenicillin. Both of these penicillins have potentantibiotic activity in warm-blooded animals. Employing these sameprocedures many synthetic penicillins and cephalosporins are preparedwhich possess valuable activity against both gram-positive andgram-negative bacteria.

The new and novel compounds of this invention (1 and ll) are also usefulin preparing new synthetic 2- amidopenicillins and 2-amidocephalosporinsusing conventional acylation procedures. For example, a2-amido-6-amino-penicillanic acids may be reacted with an acid chlorideto obtain the Z-amido derivatives of 2-ethoxy naphthyl penicillin, or anN-carboxy anhydride to obtain the 2-amido derivatives ofD(-)-ozaminobenzylpenicillin both having potent and sus tainedantibiotic activity in warm-blooded animals. Emoloying these sameprocedures synthetic Z-amido penicillins and cephalosporins are obtainedwhich possess valuable sustained activity against both grampositive andgram-negative bacteria.

In particular, the synthetic penicillins, cephalosporins,2-amidopenicillins and 2-amidocephalosporins prepared from theintermediates of the present invention may be utilized inpharmacological compositions in association with pharmacologicallyacceptable cartions and suspensions; or orally as tablets, capsules, and

the like, utilizing conventional solvents, suspensoids. excipients, andthe like. As previously indicated. when the compounds of this inventionare employed. they may be administered orally or parenterally.Naturally. the dosage of these compounds will vary somewhat with theform of administration and the particular com pound chosen. Further. itwill vary with the particular subject under treatment. In general, thecompounds of this invention are most desirably administered at dosagelevels corresponding to those commercially available penicillins andcephalosporins. Although variations from these dosages will occur, thesedosages will generally afford effective results without causing anyharmful or deleterious side effects.

The following examples are given by way of illustrating some embodimentsof this invention.

EXAMPLE 1 mole) is added. The solution is cooled to -40C. by anacetone-dry ice bath, and phosphorus pentachloride (4.54 g., 0.218 mole)is added over a few minutes under nitrogen. The solution is kept at toC.

for three hours with mechanical stirring. After approximately one-halfto one hour at this temperature, a white crystalline material formswhich is 2-[(6-[ lchloro-Z-phenoxyethylideneamino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-yl)carbonyl]-l,2-benzisothiazol3(2H)-one 1,1-dioxide, also known as the saccharimideof 6-chloroimidophenoxymethyl penicillin. Then l-butanol (75 ml.) isadded over approximately five minutes at -35 to 40C. and thistemperature is maintained for three hours to afford the hydrochloride of2-[ 6-[ l-butoxy-Z-phenoxyethylideneaminol-3,3-dimethyl-7-oxo-4-thial-azabicyclo[3.2.0]hept-2-yl)carbonyl]-1,2-benZisothiaz0l-3(2H)-one 1,1-dioxide, also named as the saccharimide of6-butoxyimidophenoxymethyl penicillin hydrochloride. Then water (40 ml.)is added to the rapidly stirred mixture allowing the temperature to riseto 05C. The mixture is then stirred at 05C. for

' one hour and kept at 0C. overnight, without stirring.

The mixture is filtered and the solid is washed with an hydrous ethergiving a white solid which is the hydrochloride of2-[(6'amino-3,3-dimethyl-7-oxo-4-thia-lazabicyclol3.2.0]hept-2-yl)carbonyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, also described as the saccharimideof 6-aminopenicillanic acid, hydrochloride (2.5 g., 29%), mp. 172C. dec.(uncorr) Analysis: Calcd for C H, r,N O S .HCl.1/2H O: C, 42.20; H,4.01; N, 9.84; S, 15.02; H O, 2.10. Found: C, 42.57; H, 3.99; N, 9.14;S, 13.40; H O, 1.99.

EXAMPLE ll2-[(6-Amino-3,3-dimethyl-7-oxo-4-thia-lazabicyclol3.2.0]hept-2-yl)carbonyl]-l,2-

benzisothiazol-3(2H)-one 1,1-dioxide hydrochloride, also described asthe saccharimide of 6- aminopenicillanic acid hydrochloride (7.64 g.,0.02 mole) is dissolved in tetrahydrofuran (60 mL) and a solution ofsodium bicarbonate (3.36 g., 0.04 mole) in water (40 ml.) is added allat once. The mixture is stirred for three and a half hours at roomtemperature giving a solution. Then the tetrahydrofuran is stripped offat 30C. under vacuum, and the resulting mixture is washed with methylenechloride. The aqueous fraction is then placed on a rotary evaporator at30C. and the methylene chloride is removed. The solution is filtered andthe pH adjusted to 3.8 with glacial acetic acid. The mixture is stirredin ice-water for twenty minutes and then filtered, giving white crystalsfor 6amino-3,3 dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylic acid, also known as 6-aminopenicillanic acid.

EXAMPLE llI 3,3-Dimethyl-7-ox0-6-(2-phenoxyacetamido)-4-thia-1-azabicyclo[3.2.0lheptane-Z-carboxylic acid, also described asphenoxymethyl penicillin, (15.1 g., 0.043 mole) is added to anhydrousmethylene chloride (150 ml.) contained in a dry 500 ml. three neck roundbottom flask equipped with a stirrer, a drying tube and a thermometerthrough a U-tube nitrogen inlet. Then triethylamine (4.34 g., 0.043mole) is added, and the solution is cooled to C. in ice. Pseudosaccharinchloride (8.7 g., 0.043 mole) is added all at once, giving a canaryyellow solution. The solution is stirred for onehalf hour at 5C., andkept at room temperature overnight. The solution is then brought to theboiling point for five minutes, and allowed to cool to room temperatureto afford 2-[(3,3-dimethyl-7oxo-6-[2-phenoxyacetamido]-4-thia-l-azabicyclo[3.2.0]hept-2 yl )carbonyl'] l,2-benzisothiazol-3(2H )one l,ldioxide, also named as the saccharimideof phenoxymethyl penicillin.

Thereafter, quinoline (14.5 g., 0.112 mole) is added and the stirredsolution containing said saccharimide and the mixture is cooled to 30C.and phosphorus pentachloride l 1.6 g., 0.056 mole) is added over a fewminutes, keeping the temperature at 30c. The mixture is stirred forthree hours at 30C. to yield 2-[(6-l-chloro-2-phenoxyethylideneamino]-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]hept-2-yl)carbonyl]-l.2-benzisothiazol-3(2H)-one 1,1-dioxide, also known as the saccharimideof 6-chloroimidophenoxymethyl penicillin. A small portion of thismixture is separated and the 6-chloroimide isolated.

Analysis: Calcd for C H ClN O S C, 51.73; H, 3.78; Cl, 6.64; N, 7.87; S,12.01. Found: C, 51.92; H, 3.91; Cl, 6.16; N, 7.76; S, 11.69.

To the remainder of above-described mixture containing said6-chloroimide, quinoline (6.6 ml., 0.056 mole) is added followed byabsolute ethanol (100 ml.) over a few minutes, keeping the temperatureat i 3C. After stirring. the mixture for one hour at *30C. thetemperature is rapidly raised to +20C. with hot water. and immediatelybrought back to 30C. and stirred for another hour. Then the temperatureis brought up to +20C. with hot water and immediately back to l0C. andstirred for one more hour to afford 2-[ (6-[lethoxy-2-phenoxyethylideneamino]-3,3- dimethyl-7-oxo-4-thial-azabicyclol 3.2.0 ]hept-2- yl)carbonyl]-l .2-benzisothiaZol3(2H )-onel,l-dioxide hydrochloride, also described as the saccharimide of6-ethoxyimidophenoxymethyl penicillin hydrochloride.

Subsequently, water (75 ml.) is added to abovedescribed mixturecontaining said -ethoxyiniide hydrochloride and the temperature islowered to 0C. and then stirred for twenty minutes. The mixture is keptat 0C. overnight and filtered. The solid is washed with cold (5C.) water(30 ml.), without slurrying the solid in the water, and sucked dry. Thesolid is then washed with cold (5C.) methylene chloride (2 X 30 ml.),slur ried in absolute ether and sucked dry on the funnel, dried over P 0in a vacuum, giving white crystals of2-1(6-amino-3,3-dimethyl-7-oxo-4-tliia-l azabicyclo[3.2.-0lhept-2-yl)carbonyll-l,2-benzisothiazol-3(2H)-one l,l-dioxide,hydrochloride, also known as the saccharimide of 6-amino-penicillanicacid, hydrochloride (11.1-12.6 g., 62-75%), mp. 176C. dec. (uncorr.).

Analysis: Calcd for C ,-,H -,N;,O -,S .HCl.l/2H O: C, 42.40; H, 4.01; N,9.84; S, 15.02; Cl, 8.30. Found: C, 42.25; H.383; N, 9.73; S, 15.1 1;Cl, 11.40.

EXAM PLE lV 2-[(6-Amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclol3.2.0lhept-2-yl)carbonyl]-l,2-

benZisothiaZol-3(2H)-one l,l-dioxide, hydrochloride (8.6 g., 0.0206mole) as prepared in Example 111, is powdered, added to water ml.) infour portions, and stirred at 0C. Adjustment to the pH to 6.9 after eachaddition is done with a 60C. saturated sodium bicarbonate solution.After the second addition some ether is added to control the foaming.After the final adjustment of the pH to 6.9 the mixture is stirred at0-2C. for 10 minutes. and the pH slowly goes to 7.1. The solid isfiltered and washed with cold water (2 X), and dried in a desiccatorover P 0 under vacuum at 5C., giving a white solid which is2-[(6-amino-3,3-

dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]hept-2-yl)carbonyl]l,2benzisothiazol-3(2H)-one 1,1- dioxide, also described asthe saccharimide of 6- aminopenicillanic acid (7.0 g., mp. 158C. dec.(uncorr.).

Analysis: Calcd for C H, -,N O,,S C, 47.23; H, 3.97; N, 11.02; S, 16.81.Found: C, 47.43; H, 3.94; N, 11.21; S, 16.60.

EXAMPLE V Following the procedure of Examples l-lV, phenoxymethylpenicillin is reacted with a series of saccharimide derivatives toafford the hereinafter listed saccharimide derivatives of phenoxymethylpenicillin, which are contacted with phosphorus pentachloride to affordthe corresponding saccharimides of 6- chloroimidophenoxymethylpenicillin which are contacted with an alkanol to yield appropriatesaccharimides of 6-alkoxyimidophenoxymethyl penicillin hydrohalides,which are then hydrolyzed and neutralized to produce the followingsaccharimides of 6- aminopenicillanic acid:

Table A Saccharimide Derivatives of Phenoxymethyl PenicillinSaccharimide Derivatives of 6-Aminopenicillanic Acid S-ethylsaccharimideof phenoxymethyl penicillin Table A :Qentina Saccharimide Derivatives ofPhenoxymethyl Penicillin 5-chloro-6-propylsaccharimide of phenoxymethylpenicillin (i-nitrosaccharimide of phenoxymethyl penicillin5,6-dibromosaccharimitle of phcnoxymethyl penicillin S-hcxylsaccharimideolphenoxymethyl penicillin 5-hutoxy-6-phenylsaccharimide ofphenoxymethyl penicillin S-(p-methoxyphenyl)sacchar imide ofphenoxymethyl penicillin S-phenylsaccharimide of phenoxymethylpenicillin o-benzylsaccharimide of phcnoxymethyl penicillin 7-(m-propoxyphenyl)sacchariniide 0f phenoxymethyl penicillin4-hutyl-5-fluorosaccharimidc olphenoxymethyl penicillin SuccharimidcDerivatives of h-Aminopenicillanic Acid 5-chloro--propylsaccharimide of(i-aminopenicillanic acid o-nitrosaccharimide of (iaminopenicillanicacid 5,(i-dihromosaccharimidc of fi-aminopenicillanic acidS-hexylsaccharimidc of (1- aniinupenicillanic acidS-butoxy-(i-phenylsaccharimidc of flaminopenlcillamc acid 5-(p-methoxyphenyl )sacchar imide of fi-aminopenicillanic acidS-phenylsaccharimide of -aminopenicillanic acid -benzylsaccharimide of-aminopenicillanic acid 7-( m-propoxyphenyl )saccharimide ofG-aminopenicillanic acid 4-butyl-S-fluorosaccharimide of6-ammopen1cillamc acid EXAMPLE Vl Repeating the procedure of ExamplesllV, to react a series of saccharimide derivatives with benzylpenicillin there is produced the hereafter set forth saccharimidederivatives of benzyl penicillin which are contacted with phosphoruspentabromide to afford the corresponding saccharimides of6-bromoimidobenzyl penicillin which are contacted with an alkanol toyield appropriate saccharimides of o-alkoxyimidobenzyl penicillinhydrobromide which are then hydrolyzed and neutralized to produce thefollowing saccharimides of 6-aminopenicillanic acid:

Table B Saccharimide Derivatives of Benzyl Penicillin 5-meth \'l-6-(Z-pyridyl) saccharimidc of benzyl penicillin5-trilluoromethylsaccharimidc of benzyl penicillin 6dimethylamino-7-methyl saccharimide of benzyl penlclllin 7-diethylaminosaccharimide of benzyl penicillin 5,6-benzosaccharimide of benzylpenicillin Saccharimidc Derivatives of 6-Aminopenicillanic Acidj-methyl-fi-l Z-pyridyl )saccharlnlKlC ol h-aminopenicillanic acidS-trilluoromethylsaccharimide of (HIminopenicillanic acido-dimethylaminn-7-methyl saccharimide of (i-annnopenicillanic acid7-diethylaminosaccharimide ol b-aminopenicillan1c acld5-carbomethoxysaccharimidc (i-aminopenicillanic acid6-sulfamidosaccharimide of fi-aminopenicillanlc acid5-carhcthoxysaccharimide of (i-ammopenlcillanic acid(i-cyanosaccharimidc of (i-aminopenicillanic acidfi-propylthiosaccharimide ol o-aminopenicillanie acid5-ethylsulfonylsaccharimide of fi-aminopenicillamc acid6-(4-pyridyl)saccharimide of fi-ammopenicillanic acid5,6benzosaccharimide of (i-aminopenicillanic acid EXAMPLE Vll6-(3-Hexenamiclo)-3,3-dimethyl-7-oxo-4-thia-lazabicyclol32.0lhcptane-Z-carboxylicacid, also de' scribed as Z-pentenyl penicillin, (0.040 mole) is addedto anhydrous methylene chloride (150 ml.) contained in a dry 500 ml.three neck round bottom flask equipped with a stirrer, a drying tube anda thermometer through a U-tube nitrogen inlet. Then triethylamine (0.040mole) is added, and the solution is cooled to 5C. in ice.Pseudosaccharin chloride (0.040 mole) is added all at once, giving ayellow solution. The solution is stirred for one-half hour at 5C., andkept at room temperature overnight. The solution is then brought to theboiling point for five minutes, allowed to cool to room temperature,filtered and the collected solid is 2-[(6-[Z-hexenamido]-3,3-dimethyl-7-oxo-4-thia-lazabicyclo[3.2.0]hept-2-yl)carbonyll-l,2-benzisothiazol-3(2H)-one l,l-dioxide, also named as the saccharimide ofZ-pentenyl penicillin.

Repeating the above procedure, to react appropriate penicillins withvarious saccharin chloride derivatives, the following penicillinsaccharimides are obtained:

2-[ 6-[ Z-allylmercaptoacetamido1-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]hept2-yl)carbonyl]-5-chloro-l,2-benzisothiazol-3(2H)-one l,l-dioxide, also known as the5-chlorosaccharimide of allylmercaptomethyl penicillin;

2-[(6-[2-(y-chlorocrotylmercapto)acetamido]-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]hept-2- yl )carbonyl]- l,2-ben2isothiazol-3( 2H )-one 1,1- dioxide, also described as thesaccharimide of y-chlorocrotylmercaptomethyl penicillin;

2-[(3,3-dimethyl-7-oxo-6-[2-phenylacetamido1-4-thia-l-azabicyclo[3.2.0]hept-2-yl)carbonyl]-l,2-benzisothiazol-3(2H)-one l,l-dioxide, also named as the saccharimide ofbenzyl penicillin;

2-! o-hexanamido-3,3-dimethyl 7-oxo-4-thia- 1a2abicyclo[3.2.0]hept-2-yl)carbonyl]-l,2- benzisothiazol3(2H)-onel,l-dioxide, also defined as the saccharimide of amyl penicillin;

2[ (3,3-dimethyl-6-octanamido-7-oxo-4-thial azabicyclol 3 .2.0]hept-2-yl)carbonyl]-l ,2- benzisothiazol-3(2H)-one l,l-dioxide, also named as thesaccharimide of heptyl penicillin; and

2-[(6-[2-(p-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4thia-l-azabicyclo[3.2.0]hept-2- yl )carbonyl1-l,2-benzisothiazol-3(2H )-one 1 ,1- dioxide, also described as thesaccharimide of hydroxybenzyl penicillin.

EXAMPLE Vlll The saccharimide of 2-pentenyl penicillin, as prepared inExample Vll, is admixed with methylene chloride (150 ml.) quinoline (0.110 mole), the stirred mixture is cooled to lC. and phosphoruspentachloride (0.055 mole) is added over a few minutes. The resultingmixture is stirred at l0C., thereafter the precipitate is separated byfiltration to yield the saccharimide of the o-chloroimido-Z-pentenylpenicillin.

In a similar manner, the other penicillin saccharimides of Example Vllare reacted with phosphorus pentahalides to afford:

-chlorosaccharimide of 6-chloroimidoallylmercaptomethyl penicillin;

saccharimide of o-bromoimido-y-chlorocrotylmercaptomethyl penicillin;

saccharimide of o-chloroimidobenzyl penicillin;

saccharimide of o-chloroimidoamyl penicillin;

saccharimide of o-chloroimidoheptyl penicillin; and saccharimide of6-chloroimidohydroxybenzyl penicillin.

EXAMPLE [X The saccharimide of the o-chloroimido-Z-pentenyl penicillin,as prepared in Example Vlll. is admixed with methylene chloride(1501111.). quinoline (0.055 mole) and absolute methanol l00 ml. keepingthe temperature at -30C. i 3C. After stirring. the mixture for one hourat 30C. the temperature is rapidly raised to +20C. with hot water, andbrought back to 30C. and stirred for another hour. Then the temperatureis brought up to +20C. with hot water and quickly back to -l0C. andstirred for one more hour to produce the saccharimide ofo-methoxyimido-Z-pcntenyl penicillin. hydrochloride which is separatedby filtration.

In like manner, the (i-haloimido penicillin saccharimides of ExampleVlll are reacted with various alkanols to yield:

saccharimide of 6-ethoxyimido-Z-pentenyl penicillin, hydrochloride;

saccharimide of 6-pentoxyimido-2-pentenyl penicillin, hydrochloride;

5-chlorosuccharimide of 6-methoxyimidoallylmercaptomethyl penicillin,hydrochloride;

5-chlorosaccharaimide of 6-ethoxyimidoallylmercaptomethyl penicillin,hydrochloride;

5-chlorosaccharimide of o-butoxyimidoallylmercaptomethyl penicillin,hydrochloride;

saccharimide of 6-methoxyimido-y-chlorocrotylmercaptomethyl penicillin,hydrobromide;

saccharimide of o-ethoxyimido-y-chlorocrotylmercaptomethyl penicillin,hydrobromide;

saccharimide of 6hexoxyimido-y-chlorocrotylmercaptomethyl penicillin,hydrobromide;

saccharimide of 6-ethoxyimidobenzyl penicillin, hydrochloride;

saccharimide of o-butoxyimidobenzyl penicillin, hy-

drochloride; v

saccharimide of o-ethoxyimidoamyl penicillin, hydrochloride;

saccharimide of o-propoxyimidoamyl penicillin, hydrochloride;

saccharimide of o-methoxyimidoamyl penicillin, hydrochloride;

saccharimide of o-methoxyimidoheptyl penicillin, hydrochloride;

saccharimide of 6-ethoxyimidoheptyl penicillin, hydrochloride;

saccharimide of o-butoxyimidoheptyl penicillin, hydrochloride;

saccharimide of 6-methoxyimidohydroxybenzyl penicillin, hydrochloride;

saccharimide of 6-ethoxyimidohydroxybenzyl peni cillin, hydrochloride;and

saccharimide of 6-butoxyimidohydroxybenzyl pcnicillin, hydrochloride.

EXAMPLE X The saccharimide of 6-methoxyimido-Z-pentenyl penicillinhydrochloride, as prepared in Example IX, is

added to methanol (100 ml.), water ml.) and the.

temperature is lowered to 0C. with stirring for one-half hour. Themixture is kept at 0C. overnight and filtered. The solid is washed withcold (5C.) water (30 ml.), without slurrying the solid in the water, anddried. The solid is then washed with cold (5C.) methylene chloride (2 X30 ml.), slurried in absolute ether and dried on the funnel, dried overP 0 in a vacuum, giving crystals of the saccharimide ofo-aminopenicillanic acid, hydrochloride.

[n the same manner, the other 6-alkoxyimido penicillin saccharimide,hydrohalides of Example IX are converted to the correspondingsaccharimide of 6- aminopenicillanic acid, hydrohalides.

When the above-prepared hydrohalides are neutralized by the procedure ofExample IV, the appropriate saccharimides of 6aminopenicillanic acid areobtained.

EXAMPLE Xl Triethylammonium 3-acetoxymethyl-8-oxo-5-thia-7-(thiophene-2-acetamido)-1-azabicyclo[4.2.0]oct-2-en- Zcarboxylate (0.040mole) is added to anhydrous methylene chloride (150 ml.) contained in adry 500 ml. three neck round bottom flask equipped with a stirrer, adrying tube and a thermometer. Thereafter, the solution is cooled to 5C.in ice and pseudosaccharin chloride (0.040 mole) is added all at once,giving a yellow solution. The solution is stirred for one-half hour at5C.. and kept at room temperature overnight. The solution is thenbrought to the boiling point for five minutes. and allowed to cool toroom temperature to afford 2-[3-hydroxymethyl-8-oxo 7-(2-thiopheneacetamido)-5-thia-l-aZabicyclo[4.2.0]oct-2- en-Z-ylcarbonyH-l,2-benzisothiazol-3(2H)-one l,l dioxide, acetate, also designated as thesaccharimide of cephalothin, mp. 160C. dec. (uncorr.).

Thereafter, quinoline (0.1 10 mole) is added to the stirred solutioncontaining said saccharimide. The mixture is cooled to 30C. andphosphorus pentachloride (ll.6 g., 0.056 mole) is added over a fewminutes, keeping the temperature at 30C. The mixture is stirred forthree hours at -30C. to yield 2-[7-(1chloro-2-[2-thienyl]ethylideneamino)-3-hydroxymethyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2- en-Z-ylcarbonyl l,2-benzisothiazol-3(2H )-one 1, l dioxide. acetate, also known as thesaccharimide of 7- chloroimidocephalothin.

To the above-described mixture containing said 7- chloroimide, quinoline(0.055 mole) is added followed by absolute ethanol (100 ml.) over a fewminutes, keeping the temperature at -30C. i 3C. After stirring, themixture for one hour at 30C. the temperature is rapidly raised to +C.with hot water, and immediately brought back -C. and stirred for anotherhour. Then the temperature is brought up to +20C. with hot water andimmediately back to l0C. and stir for one more hour to afford 2-[7-(l-ethoxy2-[2- thienyl]ethylideneamino)-3-hydroxymethyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-2-ylcarbonyl]-1,2-benzisothiazol-3(2H)-one l,l-dioxide, acetate, hydrochloride, alsodescribed as the saccharimide of 7- ethoxyimidocephalothin,hydrochloride.

Subsequently, water (75 ml.) is added to abovedescribed mixturecontaining said 7-ethoxyimide hydrochloride and the temperature islowered to 0C. and then stirred for twenty minutes. The mixture is keptat 0C. overnight and filtered. The solid is washed with cold (5C.) water(30 ml.), without slurrying the solid in the water, and sucked dry. Thesolid is then washed with cold (5C.) methylene chloride (2 X 30 ml.),slurried in absolute ether and dried on the funnel, dried over P 0 in avacuum. giving crystals of 2-[7-amino-3-hydroxymethyl-X-oxo-S-thia-l-azabicyclol4.2.0loet-2- enl-ylcarbonyl l,2-henzisothiazol-3( 2H )-one l,ldioxide. acetate. hydrochloride, alsoknown as the saccharimide of 7-aminocephalosporanic acid, hydrochloride.

EXAMPLE Xll2[7-Amino3-hydroxymethyl-8-oxo-5-thia-lazabicyclol4.2.0]oct-Zen-Z-yIcarbonyl1-1.2- benzisothiazol-3(2H)-one l,l-dioxide. acetate.hydrochloride (0.02 mole). as prepared in Example Xl. is powdered andadded to water ml.) in four portions. stirred at 0C. Adjustment of thepH to 6.9 after each addition is done with a o0C. saturated sodiumbicarbonate solution. After the second addition some ether is added tocontrol the foaming. After the final adjust ment of the pH to 6.9 themixture is stirred at 02C, for 10 minutes, and the pH slowly goes to7.1. The solid is filtered and washed with cold water (2 X), and driedin a desiccator over P ,O under vacuum at 5C.. giving a white solidwhich is 2-[7-amino-3-hydroxymethyl-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-2-ylcarbonyl1-l,2-benzisothiazol-3(2H)-one' l,ldioxide, acetate, alsodescribed as the saccharimide of 7-aminocephalosporanic acid.

EXAMPLE Xlll2-[7-Amino-3-hydroxymethyl-8-oxo-5-thia-lazabicyclo[4.2.0]oct-2-en-2-ylcarbonyl]-l,2- benzisothiazol-3(2H)-one l,l-dioxide, acetate as prepared in ExampleXII, is dissolved in tetrahydrofuran (60 ml.) and a solution of sodiumbicarbonate (0.04 mole) in water (40 ml.) is added all at once. Themixture is stirred for three hours at room temperature giving asolution. Then the tetrahydrofuran is removed at 30C. under vacuum, andthe resulting mixture is washed with methylene chloride. The aqueousfraction is than placed on a rotary evaporator at 30C. and the dissolvedmethylene chloride is removed. The solution is filtered and the pHadjusted to 3.8 with glacial acetic acid. The mixture is stirred inice-water for one-half hour and then filtered, giving crystals of7-amino-3- (hydroxymethyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid, acetate, also known as 7-aminocephalosporanicacid.

EXAMPLE XlV c H2N I s a i l\ CH3 wherein X and Y when taken separatelyare defined as follows:

EXAMPLE XVl When the procedures of Examples VII-X are re peated, aseries of 2-cycloamido derivatives of natural penicillins are preparedwhich are reacted with phosphorus pentachloride to yield theircorresponding 2- cycloamido-6-chloroimidopenicillins which are thenreacted with an alkanol to afford appropriate 2-cycloamido-6-alkoxyimidopenicillin hydrochlorides which are thenhydrolyzed and neutralized to afford 2- cycloamido-6-aminopenicillanicacids having the formula:

wherein X and Y when taken together are defined:

3-oxo-l ,2-benzisothiazolin2-yl. l,l-dioxide; 4-methoxyphthalimido;

EXAMPLE xvu O L u 1 c-u ll wherein R .is defined as follows and X and Ywhen maleimido; taken together are defined:

X and Y R' S-ethylJ-oxo-l ,Z-henzisothiazolin- CH OCOCH 2-yl, l,l-dioxidc phthalimido CH IOH sueeinimido CH 3 oxo-Z-isothiazolidinyl,LI-dioxidc CH OCOCH, 3-oxo-4-isothiazolin-Z-yl, l.l-dioxide CH OCOCH6.7-diehloro-3-oxo-4, l ,Z-henzoxathiaziw CH OCOCH 2(3H )-y| l.l-dioxidc3-oxol .4.2-henlodithiazin-2( 3H )-yl, CH OCOCH l,l-dioxide6-cyano-3,4-dihydro-4-methy|-3 oxo-2H- l, CH OH2,4-henzothiadiazin-Z-yl.l l -dioxide tetramethylsuccinimido (H 34-dihydro-2,4-dioxo-2H-l ,B-henzoxazinJ-yl CH OCOCH7-trifluoromethyl-3,4-dihydro-ZA-dioxo-ZH- CH. .OCOCH;,

l,3-benzothiazin-3-yl l,4-dihydr0- l -methyI-2,4-dioxo-3( 2H)quinazolinyl CH OH l 2-benzisothiazolin-Z-yl, l,l-dioxide CH OHS-benzyll -oxo-2-isoindolinyl CH Z-isothiazolidinyl, l, l -dioxide CHOCOCH CH: 2oxol-pyrrolidinyl CH OCOCH 3,4-dihydro-3-ox0-2H-l2-hen7.othiazin- CH 2-yl. l l-dioxide 7-carbomethoxy-3.4-dihydro-l.B-dioxo- CH OH 2( l H )-isoquinolyl o-benzenedisulfonimido CH. ,OCOCH;

succinimido; 50 EXAMPLE XVIII3,3-Dimethyl-7-oxo-6-(2-phenoxyacetamido)-4-thial-azabicyclo[3.2.0lheptane-Z-carboxylicacid, also described as phenoxymethyl penicillin is added to anhydrousmethylene chloride (2 liters) and the mixture is stirred and cooled inice to 6C. Then triethylamine (78.8 g., 0.73 mole) is added and washedin with anhydrous methylene chloride (250 ml.), causing the solid todissolve. The solution is cooled to 5C. and il4-saccharin chloride (147g., 0.73 mole) is added and washed in with anhydrous methylene chloride(250 ml.). The light yellow solution is stirred at 5l0C. for one-halfhour, and then kept at room temperature overnight. Quinoline (213 ml.,1.8 mole) is added to the stirred solution, the internal temperature isquickly lowered to -3()C. As soon as the temperature reached "30C.powdered phosphorus pentachloride (187 g., 0.90 mole) is added overabout three minutes while the temperature is maintained at 28 to 30C.The mix- 25 ture is stirred for three hours at 30C. and a solution ofquinoline (105 ml., 0.90 mole) in absolute ethanol (850 ml.) is addedover about 10 minutes, while maintaining the temperature at 27 to 30C.After stirring for one hour at -30C. the temperature is rapidly raisedto +20C., and then immediately lowered to 30C. After stirring anotherhour at 30C. the temperature is rapidly raised to +20C. and thenimmediately lowered to 10C. The temperature is maintained at -lC. forone hour, water (650 ml.) is added and the mixture stirred at 0C. for 20minutes. The mixture is stored at 0C. overnight and filtered through acoarse sintered funnel. The off-white solid is slurried three times withcold (C.) methylene chloride, three times with cold water (just enoughto cover the solid), and two times with anhydrous ether. The resultingwhite solid is spread out on paper in a hood and air-dried overnight,giving a powdery white solid which is 2-[ (6- amino-3,3dimethyl7-oxo-4-thia-1- azabicyclol3 ,2.0|hept-2-yl)carbonyl]-l ,2-benzisothiazol-M2H -one. 1,1-dioxide hydrochloride, as named as thesaccharimide of o-aminopenicillanic acid, hydrochloride (212210 g.,62%).

EXAMPLE XlX 2-[(D-[2-amino-2phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-l-azabicyclol3.2.0]hept-2-yl)carbonyl]-l,2-benzisothiazol-3(2H )-one 1,1-dioxide, also described as thesaccharimide of ampicillin, (0.02 mole) is dissolved in anhydrousmethylene chloride (75 ml.)

and N,Ndimethylaniline (0.07 mole) is added. The solution is cooled to40C. by an acetone-dry ice bath, and phosphorus pentabromide (0.218mole) is added over a few minutes under nitrogen. The solution is kept-at 35 to 40C. for three hours with mechanical stirring. Afterapproximately one-half to one hour at this temperature, a whitecrystalline material forms which is 2((D-l2-amino-l-bromo-2-phenylethylideneaminol-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3,2,0]hept-2-yl)carbonyl]-1,2-benzisothiaiol 3(2 H one 5 1,1- dioxide, also known asthe saccharimide of 6- bromoimidoampicillin. Then l-butanol (75 ml.) isadded over approximately five minutes at 35 to 40 C. and thistemperature is maintained for three hours to afford 2[ D-[ 2-aminol-butoxy-2-phenylethylideneamino]-3,3-dimethyl-7-oxo-4-thia-lazabicyclo[3 ,2,Olhept-Z- yl )carbonyl]-l ,2-benzisothiazol-3(2H )-one 1,1-dioxidehydrobromide, also named as the saccharimide of 6- butoxyimidoampicillinhydrobromide. Then water (40 ml.) is added to the rapidly stirredmixture allowing the temperature to cool to 05C. The mixture is stirredat 0-5C. for one hour and then kept at 0C. overnight, without stirring.The mixture is filtered and the solid is washed with anhydrous ethergiving a white solid which is the hydrobromide of2-[(6-amino-3,3-dimethy1-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-yl)carbonyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, scribed as the saccharimide of6-aminopenicil1anic acid, hydrobromide.

EXAMPLE XX2-1(o-Amino-3,3-dimethyl-7-oxo-4-thia'lazabicyclol3.2.0]hept-2-yl)carbonyl|-1,2-hcnzisothiuzol-3(2H)-one l,1-dioxide hydrobromide. also described as thesaccharimide of 6 aminopenicillanic acid hydrobromide (0.02 mole) isdissolved in tetrahydrofuran (60 ml.) and a solution of sodiumbicarbonate (3.36 g., 0.04 mole) in water (40 ml.) is added all at once.The mixture is stirred for three and a half hours at room temperaturegiving a solution. Then the tetrahydrofuran is stripped off at C. undervacuum, and the resulting mixture is washed with methylene chloride. Theaqueous fraction is then placed on a rotary evaporator at 30C. and themethylene chloride is removed. The solution is filtered and the pHadjusted to 3.8 with glacial acetic acid. The mixture is stirred inice-water for 20 minutes and then filtered. giving white crystals of6-amino-3,3-dimethyl-7-oxo-4- thial -azabicyclo[ 32.0]heptane-2-carboxylic acid. also known as 6-aminopenicillanic acid.

EXAMPLE XXI Saccharimide of Benzyl Penicillin ether. The filtrate of thecrystals yields an additional amount of crude yellow solid (19.5 g.).

Analysis: Calcd for C H- N O s- C, N, 8.41; S, 12.84. Found: C, 55.21;H, 4. S, 12.65; H O, 0.16.

EXAMPLE XXll The Saccharimide of Phenoxymethyl Penicillin 3,3-Dimethyl-7-oxo-6-( 2-phenoxyacetamido)-4-thial-azabicyclol3.2.0]heptane2-carboxylic acid (phenoxymethylpenicillin) (17.5 g., 0.05 mole) is added to,

anhydrous methylene chloride (750 ml.) followed by triethylamine (5.05g., 0.05 mole), giving a solution. The magnetically stirred solution iscooled to 3 in icewater. 3-Chloro- 1 ,2-benzisothiazole 1,1 ,-dioxide(10.05 g., 0.05 mole) is added all at once, giving a light yellowsolution. After stirring for /a hour in ice-water the solution is keptover night at room temperature. The solution is washed with cold water(700 ml.), cold 0.13 M/pH7.4/(K HPO /KH PO4) (500 ml.), and driedthrough sodium sulfate. The filtrate is dried over calcium sulfate, andthen concentrated at 40 under vacuum, giving a foam (24.2 g.). The foamis dissolved in 25% ether in benzene (approx. 80 ml.), giving crysalsode- Hz-H N S CH3 and HZ-H N- 2 5 v 2 r l N/SO2 z co co Z represents thehalide employed as phosphorus penwherein R is a member selected from thegroup consisting of tahalicle;

methyl, hydroxymethyl, and (lower)alkanoylox- R is selected from thegroup consisting of methyl. ymethyl; hydroxymethyl and(lower)alkanoyloxymethyl; R and R are independently members selectedfrom O O the group consisting of hydrogen and lower alkyl; 10 11 n R Cand R -C and acid addition salts thereof.

amino-X-oxo-S-thial -azabicyclol 4.2 .0 loct-Z-en-Z-ylcarbonyH-l,2-benzisothiaZol-3(2H)-one 1,1-dioxide, hydrochloride.

represent acyl moieties present in natural and synthetic penicillin andcephalosporin derivatives;

R and R, when taken separately, are independently members selected fromthe group consisting of hy- 2. The compound of claim 1,2-[3-acetoxymethyl-7- 3. The compound of claim 1, 2-[7-amino-3- drogenand lower alkyl; andhydroxymethyl-8-oxo-5-thia-l-azabicyclo[4.2.01oct-2- acid addition saltsthereof. en-Z-ylcarbonyll-l,2-benzisothiazol-3(2H)-one, 1,1- 5. Aprocess for preparing a 2-carboxy amine comdioxide, acetate.

pound having one of the formulae:

3 HN cu HN--] N -O H O 'fi" R 4. A process which comprises whichcomprises contacting a 2amido amine coma. contacting a phosphoruspentahalide in the prespound having one of the formulae:

. CH H N S 3 and HQN 2 l H l s o i 0 ,R R

N SO N SO ence of an acid acceptor and an inert organic sol- R isselected from the group consisting of methyl, vent with a compoundselected from the formulae: 5t) hydroxymethyl and(lower)alkanoyloxymethyl;

i ll S CH R -C-NH 3 and R -CNH /s 3 8 1 N R z-- R O N/SOQ O V 8 CO 9 SOb. reacting the haloimidoyl product with a lower al- R and R, when takenseparately, are independently kanol to produce a lower alkoxyimidohydrohalide; members selected from the group consisting of hy and vdrogen and lower alkyl; and c. hydrolyzing said lower alkoxyimidohydrohalicle acid addition salts thereof, with water at a pH of fromessentially by contact with water to yield a product about 1.5 to about9.0 at ambient temperature.

selected from those of the formulae: 6. A compound of the formula:

2 l l -N S0 8 R CON 2 wherein s H N- H N- 2 CH3 and 2 l r N O COZH Owhich comprises contacting a Z-amido amine com pound having one of theformulae:

X and Y, taken separately are cyano, nitro trit'luoromethylsulfonyL2,3,5,o-tetramethylbenzoyl, carbtlowerlalkoxy, di(lower)alkylcarlmmyl,lower alk \'lsulfon \l. di(lower)alkylsulfamyl.ditlower)alkylaminotlo\\'- er)alk vlsulfonyl, lower alkanoyl.cyclotlowerlalkanoyl, naphthoyl, furoyl, naphthyl sult'onyl,pyridylsulfonyl, furylsulfonyl.

wherein R and R are hydrogen, lower alkyl, halogen, trifluoromethyl,lower alkoxy, phenyl, phenoxy, nitro, lower alkylsulfonyl, or di(lower)alkylsulfamyl; R R and R are hydrogen, nitro, halogen, trifluoromethyl,lower alkoxy, lower alkylsulfonyl, lower alkylthio,di(lower)alkylsulfamyl, di(lower)alkylcarbamyl, cyano orcarb(lower)alkoxy; and the integer u is from O to 6;

and

X and Y, when taken together with the nitrogen atom CON in which R isselected from the group consisting of methyl,

hydroxymcthyl and lower )alkanoyloxymethyl;

R a ill, V I

X CON to which they are attached are selected from the group consistingof:

. H3 and CH --u wherein R and R" when taken separately are hydrogen;

31 lower alkyl; lower alkoxy; halogen; phenyl; phen(- lower)-alkyl;lower alkoxyphenyl; 2-pyridyl; 4-pyridyl; trihalomethyl; nitro;di(lower)alkylamino; sulfamido. curh( lowerlalkoxy, cyano, loweralkylthio, or lower alkylsull'onyl and when R and R" are joined, theycomplete a benzene ring fused to the existing benzene ring to formtherewith a naphthalene ring; Z is selected from the group consisting ofsulfonyl and carbonyl; W is selected from the group consisting ofsulfonyl, carbonyl and methylene; V is selected from the groupconsisting of oxygen, sulfur and methylene; u is selected from the groupconsisting of carbonyl and methylene; and the broken line indicates thepresence of a single or double bond between these two positions, withwater at a pH of from about L5 to about 9.0 at ambient temperature.

8. A process which comprises a. contacting a phosphorus pentahalide inthe presence of an acid acceptor and an inert organic solvent with acompound selected from the formulae:

0 0 ll R11 l s CH R CNH 3 and l 3 s N 1 F m /s0 s O N b. reacting thehaloimidoyl product with a lower alkanol to produce a lower alkoxyimidohydrohalide;

and c. hydrolyzing said lower alkoxyimido hydrohalide Z represents thehalide employed as phosphorus pentahalide;

R is selected from the group consisting of methyl.

hydroxymethyl and (lower)alkanoyloxymethyl;

R1 cand R ll) represent acyl moieties present in natural and syntheticpenicillin and cephalosporin derivatives.

and acid addition salts thereof.

9.'A process for preparing a 2-carboxy amine compound having'one of theformulae:

I s CH S r 1& I 3 d an 0 N 00 B 0 R1 essentially by contact with waterto yield a product selected from those of the formulae:

s H N H N-- H 3 and Y R]- N 2 N S02 which comprises contacting a Z-amidoamine compound having one of the formulae:

s 3 HZ-H N and HZ-H N- 2 3 2 N /s0 2 Q 33 34 R is selected from thegroup consisting of methyl, X and Y when taken separately are cyano,nitro, trihydroxymethyl and (lower)alkanoyloxymethyl;fluoromethylsulfonyl, 2,4,6-trimethylhenzoyl. R and R, when takenseparately, are independently 2,3,5,o-tetramethylbenzoyl, carlw(lmverlalkoxy. members selected from the group consisting ofhydi(lower)alkylcarbamyl, lower alk \'lsultlm \'l, drogen, lower alkyl,lower alkoxy, halogen, phenyl, 5 di(lower)alkylsulfantyl.di(lower)alkylaminotlowphen(lower)alkyl, lower alkoxyphenyl, Z-pyridyl.er)-alkylsulfonyl, lower alkanoyl, eyclo(lower)al- 4-pyridyl,trihalomethyl, nitro, di(lower)alkanoyl, naphthoyl, furoyl, naphthylsultonyl, pyrikylamino, sulfamido, carb(lower)alkoxy, cyano. dylgulfonyLfurylsulfonyl, lower alkylthio, lower alkylsulfonyl and when 3 joinedthey complete a benzene ring fused to the 10 R existing benzene ring toform a naphthalene ring; or and 4 acid addition salts thereof, withwater at a pH of from about 1.5 to about 9.0 at ambient temperature. 5

10. A process which comprises 15 a. contacting a phosphorus pentahalide1n the presso ence of an acid acceptor and an inert organic sol- 2 2 a'7 vent with a compound selected from the formulae:

s R C-NH and R ca F CON b. reacting the haloimidoyl product with a loweralwherein R and R are hydrogen, lower alkyl, halogen, kanol to produce alower alkoxyimido hydrohalide; 30 trifluoromethyl, lower alkoxy, phenyl,phenoxy, nitro, and lower alkylsulfonyl, or di(lower)alkylsulfamyl; R Rhydrolyzing said lower alkoxyimido hydrohalide esand R are hydrogen,nitro, halogen, trifluoromethyl, sentially by contact with water toyield a product lower alkoxy, lower alkylsulfonyl, lower alkylthio. elet d fr m h s of h fOrmulZlel di(lower)alkylsulfamyl, di(lower)allylcarbamyl, cyano S CH3 8 HZ-H N 2 CH and HZ Q WT l X 4 R O O X CON Zrepresents the halide employed as phosphorus penor carb(lower) alkoxy',and a is an integer from 0 to 6, lflhlllidfi; and X and Y, when takentogether, with the nitrogen R is selected from the group consistingofmethyl, atom to which they are attached are selected from thehydroxymethyl and (lower) alkanoyloxymethyl; group consisting of:

9 R w R 0 I Z CH M /N and u 0 wherein R and R when taken separately canbe hydro lo 11 gen; lower alkyl', lower alkoxy; halogen; phenyl; ph en(-R -C- and R C lower)-alkyl; lower alkoxyphcnyl; Z-pyrrdyl; 4pyrldyl;trihalomethyl; nitro; di(lower)alkylamino; sulfamido, represent acylmoieties present in natural and synthetic carb-(lower)alkoxy, cyano,lower alkylthio, lower alpenicillin and cephalosporin derivatives; andkylsull'onyhand when R and R are joined, they comsisting of oxygen,sulfur and methylene; u is selected from the group consisting ofcarbonyl and methylene; and the broken line indicates the presence of asingle or double bond between these two positions.

* l= l l

1. A COMPOUND OF THE FORMULA:
 2. The compound of claim 1,2-(3-acetoxymethyl-7-amino-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-en-2-ylcarbonyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, hydrochloride. 3.The compound of claim 1,2-(7-amino-3-hydroxymethyl-8-oxo-5-thia-1-azabicyclo(4.2.0)oct-2-en-2-ylcarbonyl)-1,2-benzisothiazol-3(2H)-one, 1,1-dioxide, acetate.
 4. Aprocess which comprises a. contacting a phosphorus pentahalide in thepresence of an acid acceptor and an inert organic solvent with acompound selected from the formulae:
 5. A process for preparing a2-carboxy amine compound having one of the formulae:
 6. A compound ofthe formula:
 7. A process for preparing a 2-carboxy amine compoundhaving one of the formulae:
 8. A process which comprises a. contacting aphosphorus pentahalide in the presence of an acid acceptor and an inertorganic solvent with a compound selected from the formulae:
 9. A processfor preparing a 2-carboxy amine compound having one of the formulae: 10.A process which comprises a. contacting a phosphorus pentahalide in thepresence of an acid acceptor and an inert organic solvent with acompound selected from the formulae: